Rheumatoid Arthritis: Ilowite NT

Eberhard BA, Ilowite NT. · No affiliation provided · J Rheumatol. · Pubmed #15868605 links to  free full text

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Sood SK, Ilowite NT. · No affiliation provided · J Rheumatol. · Pubmed #10955321 No free full text.

This publication has no abstract.

Ilowite NT. · Albert Einstein College of Medicine, Division of Rheumatology, Children's Hospital at Montefiore, Department of Pediatrics, Bronx, New York 10467-2490, USA. · Curr Opin Rheumatol. · Pubmed #18698187 No free full text.

Abstract: PURPOSE OF REVIEW: The purpose of this review is to summarize the recent data on biologic therapies in juvenile rheumatoid arthritis. The armamentarium for treatment of juvenile idiopathic arthritis is expanding at a rapid rate, and improved physical and functional outcomes are anticipated. New data from large prospective randomized trials have demonstrated efficacy of anti-tumor necrosis factor agents and a costimulator signal inhibitor. RECENT FINDINGS: The results of a pivotal trial of infliximab in polyarticular juvenile idiopathic arthritis suggested efficacy, but the primary outcome was not significantly different from placebo. Important information regarding dosing in children was obtained, however. A pivotal trial of adalimumab did prove efficacy, and resulted in U.S. Food and Drug Administration (FDA) approval. The monoclonal antibodies to tumor necrosis factor appear to be more effective in treating chronic uveitis associated with juvenile idiopathic arthritis than etanercept. Anti-IL-1 and anti-IL-6 therapy, particularly for systemic disease patients, looks very promising, as well. The costimulation modifier abatacept was shown to be effective and relatively well tolerated in the short term, also resulting in FDA approval this year. Continued experience with these agents and appropriate systems-based methods such as formal registries, to complement existing FDA procedures for monitoring safety, will improve our ability to identify short-term and long-term toxicities of these new agents. SUMMARY: As experience is gained, and longer-term safety is demonstrated, it is likely that biologics will be introduced as therapy earlier in the course of patients who inadequately respond to conventional disease-modifying antirheumatic drugs.

Weiss JE, Ilowite NT. · Division of Pediatric Rheumatology, Schneider Children's Hospital, 269-01 76th Avenue, New Hyde Park, NY 11040, USA. · Pediatr Clin North Am. · Pubmed #15820374 No free full text.

Abstract: Juvenile idiopathic arthritis (JIA), a term referring to a group of disorders characterized by chronic arthritis, is the most common chronic rheumatic illness in children and is a significant cause of short- and long-term disability. This article discusses the classification, differential diagnosis, and treatment of JIA.

Ilowite NT. · Division of Rheumatology, Schneider Children's Hospital, New Hyde Park, New York, USA. · Pediatrics. · Pubmed #11773549 links to  free full text

Abstract: Prognostic factors in juvenile rheumatoid arthritis (JRA) include polyarticular onset, polyarticular disease course, and rheumatoid factor positivity; in the systemic onset subtype, persistence of systemic features at 6 months after onset confers a worse prognosis. Timely diagnosis and appropriate aggressive treatment of patients with poor prognostic features improve quality of life and outcome. After nonsteroidal anti-inflammatory drugs, methotrexate is the most commonly used second-line agent. However, approximately one third of patients do not respond to methotrexate adequately. Randomized, placebo-controlled, clinical trials in patients with JRA are few, but one such trial with the tumor necrosis factor inhibitor etanercept shows that this drug is effective and well-tolerated. Other recently approved agents for rheumatoid arthritis, including infliximab, leflunomide, celecoxib, and rofecoxib, have not been adequately studied in pediatric patients, and the role of these agents in children with JRA remains to be determined.

Lovell DJ, Giannini EH, Reiff A, Jones OY, Schneider R, Olson JC, Stein LD, Gedalia A, Ilowite NT, Wallace CA, Lange M, Finck BK, Burge DJ, Anonymous00012. · Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. · Arthritis Rheum. · Pubmed #12528122 links to  free full text

Abstract: OBJECTIVE: To evaluate the long-term efficacy and safety of etanercept in children with juvenile rheumatoid arthritis (JRA) participating in an ongoing multicenter, open-label, extended-treatment trial. All patients had been participants in an initial randomized efficacy and safety trial of etanercept. METHODS: Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice each week. Safety and efficacy evaluations were performed every 3-4 months. The JRA 30% definition of improvement (DOI) was defined as improvement of > or =30% in at least 3 of 6 response variables used to assess disease activity, with no more than 1 variable worsening by more than 30%. RESULTS: At the time of analysis, 48 of the 58 patients (83%) were still enrolled in the study; 43 of them (74%) had completed 2 years of treatment. Of these 43 patients, 81% met the JRA 30% DOI, 79% met the JRA 50% DOI, and 67% met the JRA 70% DOI. Ten children started low-dose methotrexate after year 1. Of the 32 children taking prednisone, the dosage was decreased to <5 mg/day in 26 (81%). Two children had serious infections (varicella with aseptic meningitis in one and complicated sepsis in the other). In general, adverse events were of the types seen in a general pediatric patient population. CONCLUSION: Children with severe, longstanding, methotrexate-resistant polyarticular JRA demonstrated sustained clinical improvement with >2 years of continuous etanercept treatment. Etanercept was generally well-tolerated. There were no increases in the rates of adverse events over time. However, children taking etanercept should be monitored closely for infections.

Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, Ilowite NT, Wallace CA, Whitmore J, Finck BK. · Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. · N Engl J Med. · Pubmed #10717011 links to  free full text

Abstract: BACKGROUND: We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. METHODS: Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. RESULTS: At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. CONCLUSIONS: Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

Barnes MG, Grom AA, Thompson SD, Griffin TA, Pavlidis P, Itert L, Fall N, Sowders DP, Hinze CH, Aronow BJ, Luyrink LK, Srivastava S, Ilowite NT, Gottlieb BS, Olson JC, Sherry DD, Glass DN, Colbert RA. · Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio. · Arthritis Rheum. · Pubmed #19565513 No free full text.

Abstract: OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.

Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin SL, Baumgartner SW, Giannini EH, Anonymous00023. · Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. · Arthritis Rheum. · Pubmed #18438876 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety and efficacy of up to 8 years of etanercept treatment in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). METHODS: Patients with JRA who previously participated in a randomized controlled trial (RCT) of etanercept were eligible to receive etanercept in a long-term open-label extension (OLE) trial. Safety end points included the incidences of serious adverse events (SAEs), medically important infections (MIIs), and death. Efficacy end points included the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement. RESULTS: Of the 69 patients originally enrolled in the RCT, 58 (84%) participated in the OLE, for a total of 318 patient-years of etanercept exposure. A total of 42 of the 58 patients (72%) entered the fourth year of continuous etanercept treatment, and 26 patients (45%) entered the eighth year. Sixteen patients (23% of those entering the RCT) reported 39 SAEs. The overall rate of SAEs (0.12 per patient-year) did not increase with long-term exposure to etanercept. The rate of MIIs (0.03 per patient-year) remained low; 1 new MII was reported in patients with > or =5 years of etanercept exposure. No cases of tuberculosis, opportunistic infections, malignancies, lymphomas, lupus, demyelinating disorders, or deaths were reported. An ACR Pedi 70 response or higher was achieved by 100% of patients with 8 years of data (11 of 11) and by 61% of patients according to the last observation carried forward data (28 of 46). CONCLUSION: These data suggest that the acceptable safety profile of etanercept therapy is maintained for up to 8 years in this population of JRA patients. Improvements in the signs and symptoms of JRA were also maintained for up to 8 years.

Sacks JJ, Helmick CG, Luo YH, Ilowite NT, Bowyer S. · Centers for Disease Control and Prevention, Atlanta, Georgia 30341-3724, USA. · Arthritis Rheum. · Pubmed #18050185 links to  free full text

Abstract: OBJECTIVE: To estimate the prevalence of and the annual number of ambulatory health care visits for pediatric arthritis and other rheumatologic conditions. METHODS: We used physician office visit, outpatient department visit, and emergency department visit data from the 2001-2004 National Ambulatory Medical Care Survey and 2001-2004 National Hospital Ambulatory Medical Care Survey to estimate annual visits for the International Classification of Diseases, Ninth Revision, Clinical Modification codes thought to represent significant pediatric arthritis and other rheumatologic conditions (SPARC). We converted visit estimates into prevalence estimates using data on the number of prior annual visits per patient. Synthetic estimates for states were produced using national rates. RESULTS: The average annualized estimate of the number of children with SPARC was 294,000 (95% confidence interval [95% CI] 188,000-400,000). The annualized number of ambulatory health care visits for SPARC was 827,000 (95% CI 609,000-1,044,000). CONCLUSION: Pediatric arthritis estimates have varied widely because it is an umbrella term for which there are many definitions and because it is a relatively uncommon condition from a population surveillance perspective. Our estimates suggest that arthritis-related health care visits impose a substantial burden on the pediatric health care system. One advantage of this surveillance paradigm is that it has established a starting point for tracking the national prevalence of arthritis and rheumatologic conditions in children on an ongoing basis using existing infrastructure rather than expensive new surveys. This surveillance system will help us monitor and predict the health care needs of patients with these conditions.

Fall N, Barnes M, Thornton S, Luyrink L, Olson J, Ilowite NT, Gottlieb BS, Griffin T, Sherry DD, Thompson S, Glass DN, Colbert RA, Grom AA. · Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. · Arthritis Rheum. · Pubmed #17968951 links to  free full text

Abstract: OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome. METHODS: Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples. RESULTS: Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a. CONCLUSION: These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.

Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT, Brunner HI, Griffin T, Graham TB, Sherry DD, Passo MH, Ramanan AV, Filipovich A, Grom AA. · Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. · Arthritis Rheum. · Pubmed #17328073 links to  free full text

Abstract: OBJECTIVE: Macrophage activation syndrome is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. Levels of soluble interleukin-2 receptor alpha (sIL-2Ralpha) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages, respectively. This study was undertaken to assess the value of serum sIL-2Ralpha and sCD163 in diagnosing acute macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (JIA). METHODS: Enzyme-linked immunosorbent assay was used to assess sIL-2Ralpha and sCD163 levels in sera from 7 patients with acute macrophage activation syndrome complicating systemic JIA and 16 patients with untreated new-onset systemic JIA. The results were correlated with clinical features of established macrophage activation syndrome, including ferritin levels. RESULTS: The median level of sIL-2Ralpha in the patients with macrophage activation syndrome was 19,646 pg/ml (interquartile range [IQR] 18,128), compared with 3,787 pg/ml (IQR 3,762) in patients with systemic JIA (P = 0.003). Similarly, the median level of sCD163 in patients with macrophage activation syndrome was 23,000 ng/ml (IQR 14,191), compared with 5,480 ng/ml (IQR 2,635) in patients with systemic JIA (P = 0.017). In 5 of 16 patients with systemic JIA, serum levels of sIL-2Ralpha or sCD163 were comparable with those in patients with acute macrophage activation syndrome. These patients had high inflammatory activity associated with a trend toward lower hemoglobin levels (P = 0.11), lower platelet counts, and significantly higher ferritin levels (P = 0.02). Two of these 5 patients developed overt macrophage activation syndrome several months later. CONCLUSION: Levels of sIL-2Ralpha and sCD163 are promising diagnostic markers for macrophage activation syndrome. They may also help identify patients with subclinical macrophage activation syndrome.

Lovell DJ, Reiff A, Jones OY, Schneider R, Nocton J, Stein LD, Gedalia A, Ilowite NT, Wallace CA, Whitmore JB, White B, Giannini EH, Anonymous00068. · Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. · Arthritis Rheum. · Pubmed #16732547 links to  free full text

Abstract: OBJECTIVE: Previous studies showed that etanercept treatment in patients with polyarticular-course juvenile rheumatoid arthritis (JRA) provided rapid clinical improvement that was sustained for up to 2 years. The goal of our study was to provide data on safety and efficacy after 4 years of etanercept treatment in patients with JRA. METHODS: Patients with active polyarticular-course JRA who participated in an efficacy study continued etanercept treatment in an open-label extension. Safety was assessed by measuring rates of serious adverse events (SAEs) and serious infections. Efficacy was assessed using the American College of Rheumatology (ACR) Pediatric 30 criteria for improvement and standard measures of disease activity. (The ACR Pediatric 30 criteria are defined as improvement of > or = 30% in at least 3 of 6 core response variables used to assess disease activity, with no more than 1 variable worsening by > or = 30%.) RESULTS: Of the 69 patients who enrolled in the original efficacy study, 58 patients (84%) enrolled in the extension, 34 patients received etanercept treatment for > or = 4 years, and 32 of these received complete efficacy assessments. The rate of SAEs was 0.13 per patient-year, and the rate of serious infections was 0.04 per patient-year, in a total etanercept exposure of 225 patient-years. Eighty-two percent of patients who received corticosteroids at any time during the extension were able to decrease their dosage to < or = 5 mg/day prednisone equivalent. Of the 32 patients with complete efficacy data who received etanercept for > or = 4 years, 94% achieved an ACR Pediatric 30 response and 78% achieved an ACR Pediatric 70 response at the last study visit. CONCLUSION: Etanercept offers an acceptable safety profile in children with polyarticular-course JRA and provides significant improvement in disease manifestations that are sustained for > or = 4 years.

Eberhard BA, Sison MC, Gottlieb BS, Ilowite NT. · Division of Rheumatology, Schneider Children's Hospital, 269-01 76th Avenue, New Hyde Park, NY 11040, USA. · J Rheumatol. · Pubmed #15570659 No free full text.

Abstract: OBJECTIVE: To compare patients with juvenile rheumatoid arthritis (JRA) injected with triamcinolone hexacetonide (TH) or triamcinolone acetonide (TA) with respect to time to relapse. METHODS: This was a retrospective chart review of 85 patients: 51 patients with JRA who had received a joint injection with TH during the period June 2000-April 2001 and 48 patients who had received a joint injection with TA during the period May 2001-March 2002 who were followed for a minimum of 15 months, after an intraarticular steroid injection. RESULTS: The primary endpoint variable for the study was the time to relapse of the arthritis in the affected joint following an intraarticular injection. A total of 227 joints were injected, 114 with TH and 113 with TA. In the TH group the mean time to relapse (+/- SE) was 10.14 +/- 0.49 months compared to the TA group at 7.75 +/- 0.49 months (p < 0.0001) using the log-rank test. A proportional hazards (Cox) regression analysis revealed no statistical association between sex, duration of illness, or type of arthritis and relapse time. An analysis was performed on the first intraarticular injection for each patient, with the average time to relapse for all joints injected of 10.36 +/- 0.72 months for TH compared to 8.45 +/- 0.78 months for TA (p < 0.02). A further analysis of the first knee injections showed a relapse time in the TH group of 11.11 +/- 0.81 months compared to 7.95 +/- 0.95 months for TA (p < 0.008). CONCLUSION: TH offers an advantage to TA, as there is a longer duration of action leading to an improved prolonged response rate in weight-bearing joints, particularly the knees. The results suggest that TH should be the intraarticular steroid of choice, particularly for the knee joint, in patients with JRA.

Degotardi PJ, Revenson TA, Ilowite NT. · Graduate School, City University of New York, USA. · Arthritis Care Res. · Pubmed #11081000 No free full text.

Abstract: OBJECTIVE: To explore the viability of a quantitative family interview to describe family-level coping strategies used to deal with juvenile rheumatoid arthritis (JRA)-related stressors for early and late adolescents. METHOD: A structured interview protocol with 30 adolescents with JRA and family members assessed ways JRA disrupts or changes family functioning. Emotional reactions, sequential phases of family response, and treatment adherence were discussed. Interviews were coded for family-level coping. To assess adjustment, family members completed the Youth Self Report and the Family Environment Scale. The pediatric rheumatologist provided medical information. RESULTS: The family interview produced both quantitative and qualitative data. Families reported multiple JRA-related stressors (mean 6.6). For many adolescents, treatment adherence was problematic. Families used all 3 types of coping strategies (appraisal-, problem-, and emotion-focused) to varying degrees. Problem-focused approaches were most commonly used and included seeking support (used by 73% of families), self-reliance (70%), and family coordination (70%) for dealing with specific problems, and seeking information about JRA (67%). Emotion-focused approaches, such as impulsive outbursts and diminished awareness of others' feelings, were associated with problematic adjustment. Few differences were found between the families of early and late adolescents. CONCLUSION: The quantitative family interview has the potential to be a useful tool in documenting JRA-related stressors, family-level coping processes, and how family-level coping is associated with treatment adherence and psychosocial adjustment.